Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries. MicroRNAs (miRNAs) are endogenous, small, non-coding RNAs that downregulate the expression of specific proteins. Several miRNAs are dysregulated in PCOS women, and a few have been implicated in PCOS metabolic manifestations. MicroRNA-21 (miR-21) is an attractive target because it is one of the most upregulated circulating miRNAs in PCOS subjects and experimental animal models of PCOS. miR-21 is highly expressed and dynamically regulated in multiple tissues important in women and animal models of PCOS, including adipose tissue, liver and muscle that have been implicated in the metabolic dysfunction observed in PCOS. miR-21 is upregulated by androgens sine the activated androgen receptor directly binds to the miR-21 promoter. In addition, the PI3K/PTEN/Akt signaling pathway plays a central role in insulin signaling, and PTEN is a miR-21 target gene. In this proposal we will test the hypothesis that in PCOS, elevated circulating androgens, via the androgen receptor, upregulate microRNA-21 that targets and downregulates PTEN, causing upregulation of Akt activity and dysregulation of insulin intracellular signaling leading to obesity and insulin resistance. Moreover, activation of the androgen receptor increases food intake leading to obesity in PCOS which causes a positive feedback on insulin resistance?.